Multisite phosphorylation by Cdk1 initiates delayed negative feedback to control mitotic transcription

Asfaha, Jonathan B.; Örd, Mihkel; Carlson, Christopher R.; Faustova, Ilona; Loog, Mart; Morgan, David

doi:10.1016/j.cub.2021.11.001

Cited by 12 publications

(20 citation statements)

References 46 publications

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“…This regulatory mode is such that a progressive activation of the Forkhead/Clb3 axis – possibly mediated by an increasing Clb/Cdk1-mediated multi-site phosphorylation of the Fkh2 transcription factor 102 – controls the timing of cell cycle progression. While the present article was in press, a manuscript has appeared showing that the Fkh2 coactivator, Ndd1, undergoes multi-site phosphorylation by Clb3/Cdk1 and Clb2/Cdk1 – although to a different extent, with Clb2 being more effective than Clb3 – to regulate its degradation at cell cycle exit 114 . This evidence supports that multi-site phosphorylation by sequential activation of Clb/Cdk1 complexes modulates the timing of cell cycle dynamics 102 .…”

Section: Introductionmentioning

confidence: 76%

Cyclin/Forkhead-mediated coordination of cyclin waves: an autonomous oscillator rationalizing the quantitative model of Cdk control for budding yeast

Barberis

2021

npj Syst Biol Appl

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Networks of interacting molecules organize topology, amount, and timing of biological functions. Systems biology concepts required to pin down ‘network motifs’ or ‘design principles’ for time-dependent processes have been developed for the cell division cycle, through integration of predictive computer modeling with quantitative experimentation. A dynamic coordination of sequential waves of cyclin-dependent kinases (cyclin/Cdk) with the transcription factors network offers insights to investigate how incompatible processes are kept separate in time during the eukaryotic cell cycle. Here this coordination is discussed for the Forkhead transcription factors in light of missing gaps in the current knowledge of cell cycle control in budding yeast. An emergent design principle is proposed where cyclin waves are synchronized by a cyclin/Cdk-mediated feed-forward regulation through the Forkhead as a transcriptional timer. This design is rationalized by the bidirectional interaction between mitotic cyclins and the Forkhead transcriptional timer, resulting in an autonomous oscillator that may be instrumental for a well-timed progression throughout the cell cycle. The regulation centered around the cyclin/Cdk–Forkhead axis can be pivotal to timely coordinate cell cycle dynamics, thereby to actuate the quantitative model of Cdk control.

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Section: Introductionmentioning

confidence: 76%

Cyclin/Forkhead-mediated coordination of cyclin waves: an autonomous oscillator rationalizing the quantitative model of Cdk control for budding yeast

Barberis

2021

npj Syst Biol Appl

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“…RNAs, specific proteins) in early mitosis. Indeed, CDK1 activity has been suggested to drive a transient increase in protein and RNA content in early mitosis ( Asfaha et al, 2022 ; Clemm von Hohenberg et al, 2022 ; Miettinen et al, 2019 ; Shuda et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Single-cell monitoring of dry mass and dry mass density reveals exocytosis of cellular dry contents in mitosis

Miettinen

Lam

Manalis

2022

eLife

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Cell mass and composition change with cell cycle progression. Our previous work characterized buoyant mass dynamics in mitosis (Miettinen et al., 2019), but how dry mass and cell composition change in mitosis has remained unclear. To better understand mitotic cell growth and compositional changes, we develop a single-cell approach for monitoring dry mass and the density of that dry mass every ~75 s with 1.3% and 0.3% measurement precision, respectively. We find that suspension grown mammalian cells lose dry mass and increase dry mass density following mitotic entry. These changes display large, non-genetic cell-to-cell variability, and the changes are reversed at metaphase-anaphase transition, after which dry mass continues accumulating. The change in dry mass density causes buoyant and dry mass to differ specifically in early mitosis, thus reconciling existing literature on mitotic cell growth. Mechanistically, cells in early mitosis increase lysosomal exocytosis, and inhibition of lysosomal exocytosis decreases the dry mass loss and dry mass density increase in mitosis. Overall, our work provides a new approach for monitoring single-cell dry mass and dry mass density, and reveals that mitosis is coupled to extensive exocytosis-mediated secretion of cellular contents.

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“…For example, an L-x-F motif on some substrates docks at a site called the hydrophobic patch of cyclin B 11 . The timing of substrate phosphorylation is also determined, at least in part, by the level of CDK activity, such that certain substrates are modified earlier in the cycle at low CDK activity and other substrates are modified later by rising levels of activity 4,5,7,8,12,13 . Phosphatase specificity for different sites is also likely to contribute to the timing of phosphorylation 14–19 .…”

Section: Introductionmentioning

confidence: 99%

“…We showed recently that mutation of the PP in budding yeast Clb2 reduces phosphorylation of Ndd1, a transcriptional co-activator that stimulates CLB2 expression in early mitosis 7 . Ndd1 has 16 consensus CDK phosphorylation sites.…”

Section: Introductionmentioning

confidence: 99%

Phosphate-binding pocket on cyclin B governs CDK substrate phosphorylation and mitotic timing

Ng,

Adly,

Whelpley

et al. 2024

Preprint

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SummaryCell cycle progression is governed by complexes of the cyclin-dependent kinases (CDKs) and their regulatory subunits cyclin and Cks1. CDKs phosphorylate hundreds of substrates, often at multiple sites. Multisite phosphorylation depends on Cks1, which binds initial priming phosphorylation sites to promote secondary phosphorylation at other sites. Here, we describe a similar role for a recently discovered phosphate-binding pocket (PP) on B-type cyclins. Mutation of the PP in Clb2, the major mitotic cyclin of budding yeast, alters bud morphology and delays the onset of anaphase. Using phosphoproteomicsin vivoand kinase reactionsin vitro, we find that mutation of the PP reduces phosphorylation of several CDK substrates, including the Bud6 subunit of the polarisome and the Cdc16 and Cdc27 subunits of the anaphase-promoting complex/cyclosome. We conclude that the cyclin PP, like Cks1, controls the timing of multisite phosphorylation on CDK substrates, thereby helping to establish the robust timing of cell-cycle events.

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Multisite phosphorylation by Cdk1 initiates delayed negative feedback to control mitotic transcription

Cited by 12 publications

References 46 publications

Cyclin/Forkhead-mediated coordination of cyclin waves: an autonomous oscillator rationalizing the quantitative model of Cdk control for budding yeast

Cyclin/Forkhead-mediated coordination of cyclin waves: an autonomous oscillator rationalizing the quantitative model of Cdk control for budding yeast

Single-cell monitoring of dry mass and dry mass density reveals exocytosis of cellular dry contents in mitosis

Phosphate-binding pocket on cyclin B governs CDK substrate phosphorylation and mitotic timing

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